John Buza

Does progranulin account for the opposite effects of etanercept and infliximab/adalimumab in osteoarthritis?: Comment on Olson et al.: "Therapeutic Opportunities to Prevent Post-Traumatic Arthritis: Lessons From the Natural History of Arthritis After Articular Fracture".

Dear Editors: We read with great interest the recent article by Guilak et al1, which summarizes the significant advancements that have been made in our understanding of the development of post-traumatic arthritis (PTOA) after articular fracture (AF). We would like to congratulate the authors on their significant contributions to this field, including the development of a murine model of AF2, the assessment of histologic changes and quantitative synovial fluid biomarker concentrations involved in PTOA3,4, and the identification of pharmacologic agents that can lessen the severity of PTOA after AF5,6. We were most interested in the authors recent study on the use of anti-cytokine therapy to prevent PTOA, in which the authors hypothesized that the intra-articular inhibition of IL-1, TNF-α, or both would prevent the development of PTOA after AF6. The authors demonstrated that sustained local inhibition of IL-1 by Interleukin-1 Receptor antagonist (IL-1RA, anakinra, Kineret®) reduced the severity of arthritic changes in both the cartilage and synovium after AF. Paradoxically, however, the authors found that the local inhibition of TNF-α using soluble tumor necrosis factor receptor II (sTNFRII, etanercept, Enbrel®) resulted in detrimental effects on bone morphology, cartilage degeneration, and synovial inflammation6. There has been much interest in the role of TNF-α in the development of PTOA, as it is significantly up-regulated after fracture4,7 and is associated with chondrocyte destruction and death8. There exists two distinct receptors for TNF-α, TNFR1 and TNFR29,10. Although these receptors bind to TNF-α with almost equal affinity, they have been shown to mediate different intracellular pathways. TNFR1 recruits TRADD, TRAF-2, and FADD, and activates an inflammatory response11. While TNFR2 signaling is less well understood, several studies have shown that TNFR2 instead mediates an anti-inflammatory response12,13. Using mouse models of inflammatory arthritis, investigators have shown that TNFR2 has an immunoregulatory role in reducing inflammation and preventing bone destruction12,14. Studies from other fields have confirmed these findings, as TNF-α induced cardiomyopathy and heart failure is mediated largely through TNFR1, whereas TNFR2 has been shown to have cardioprotective effects15. Studies from our laboratory also reveal the differential role of TNFR1 and TNFR2 in fracture healing and OA16-18. Our area of focus has been on a molecule termed progranulin (PGRN), a potent anti-inflammatory growth factor19-23. Interestingly, our global genetic screen for PGRN-associated proteins led to the discovery of TNFRs as PGRN-binding receptors16. PGRN and TNFα showed comparable binding affinity to TNFR1, in contrast, PGRN had an approximately 600-fold higher binding affinity for TFNR2 than TNFα16. Since PGRN and TNFα compete for binding to the same extracellular CRD2 and CRD3 domains of TNFR24, PGRN acts as a physiological antagonist of TNFα and disturbs the binding of TNFα and TNFRs16. More importantly, PGRN also acts as an optimal ligand of TNFR2 and directly activates the PGRN/TNFR2 protective and anti-inflammatory pathway. We have demonstrated that TNFR2 is critical for PGRN-mediated protection in OA development and bone fracture healing17,18,25. Another group recently showed that Atsttrin, an engineered protein composed of three TNFR-binding fragments of PGRN, ameliorated OA development in a surgically-induced mouse model26. In brief, PGRN and its derived Atsttrin appear to exert their anti-inflammatory and protective activities in OA by activation of the PGRN/TNFR2 protective/anabolic pathway12,14,27-29, and by inhibition of TNFα/TNFR1 inflammatory/catabolic signaling17,26. Etanercept (Enbrel) is a fusion-soluble TNFR2 extracellular protein, and therefore inhibits both TNFα and PGRN. PGRN may be even more inhibited than TNFα, as PGRN has a much higher binding affinity to TNFR2 than TNFα16. In this way, Etanercept may be blocking PGRN’s protective and anti-inflammatory effect against the development of OA. This would explain the detrimental effects of Etanercept in OA observed by Olson et al1,6. Unlike Etanercept, mouse TNFα monoclonal antibody (Infliximab, Remicade) and humanized TNFα monoclonal antibody (Adalimumab, Humira) are specific for TNFα, and have been shown to be protective against the development of OA in animal models30-32. This is supported by clinical trials in which Infliximab and Adalimumab have been reported to alleviate symptoms of OA33-35. The opposing effects of TNFα-specific (i.e. Infliximab and Adalimumab) and non-specific (i.e. Etanercept) inhibitors in OA indicate the critical role of other ligand(s) of TNFR, such as PGRN, in the regulation of OA. TNFα is known to be the dominant inflammatory molecule in the pathogenesis of rheumatoid arthritis, and blocking TNFα with Etanercept is thus beneficial to the patients with rheumatoid arthritis. However, in the case of OA, the PGRN/TNFR2 protective/anabolic pathway is likely to outweigh the TNFα/TNFR1 inflammatory/catabolic pathway in regulating OA development. Therefore, blocking both PGRN and TNFα with Etanercept may lead to more severe OA. In summary, the findings of Guilak et al on the negative effect of Etanercept in OA1,6, reports on the positive role of Infliximab and Adalimumab in OA30-32, and our data on PGRN-mediated protection in OA through TNFR signaling16,17, all suggest a complex interplay between TNFα, PGRN and their receptors in the pathogenesis of OA. Future studies are warranted to clarify these molecular mechanisms, which will not only better our understanding of TNFR signaling in the pathogenesis of OA, but may lead to innovative therapies for OA and other degenerative joint diseases via selectively targeting distinct TNFR pathways.

Mechanisms of anterior-posterior stability of the knee joint under load-bearing

The anterior-posterior (AP) stability of the knee is an important aspect of functional performance. Studies have shown that the stability increases when compressive loads are applied, as indicated by reduced laxity, but the mechanism has not been fully explained. A test rig was designed which applied combinations of AP shear and compressive forces, and measured the AP displacements relative to the neutral position. Five knees were evaluated at compressive loads of 0, 250, 500, and 750N, with the knee at 15° flexion. At each load, three cycles of shear force at ±100N were applied. For the intact knee under load, the posterior tibial displacement was close to zero, due to the upward slope of the anterior medial tibial surface. The soft tissues were then resected in sequence to determine their role in AP laxity. After anterior cruciate ligament (ACL) resection, the anterior tibial displacement increased significantly even under load, highlighting its importance in stability. Meniscal resection further increased displacement but also the vertical displacement increased, implying the meniscus was providing a buffering effect. The PCL had no effect on any of the displacements under load. Plowing cartilage deformation and surface friction were negligible. This work highlighted the particular importance of the upward slope of the anterior medial tibial surface and the ACL to AP knee stability under load. The results are relevant to the design of total knees which reproduce anatomic knee stability behavior.

Navigation and Robotics in Total Hip Arthroplasty

Navigation provides information about patient anatomy and the relative positioning of the implants to guide the surgeon.Some systems use a robotic arm that assists with specific parts of the procedure on the basis of anatomical information provided to the navigation system. Currently, all total hip

Navigation and Robotics in Knee Arthroplasty

Computer-assisted surgery for total knee arthroplasty can be performed with use of computer-assisted navigation, handheld navigation, partially or fully robot-assisted technology, and patient-specific instrumentation.Computer-assisted navigation leads to improved component alignment and a reduction

The effect of smoking on ACL reconstruction: a systematic review

ABSTRACT Objective: Anterior cruciate ligament reconstruction (ACLR) depends on proper healing of the graft or bone plug at the cellular level. The effect of cigarette smoke on ACLR was not commonly reported until recently. The primary purpose of this review was to determine if smoking has a negative effect on subjective or objective outcome scores after ACLR. The secondary purpose was to identify any increased risk of complications, infection, ACL re-tear, or revision procedures. Methods: A systematic literature review of the MEDLINE, SCOPUS and PubMed databases was performed to identify all studies that compared outcomes of ACLR surgery between smokers and nonsmokers. The frequency-weighted mean was calculated for outcome measures that were similar across several studies. Results: Seventeen studies were identified that met inclusion criteria for patients undergoing ACLR (mean age, 26.8 years) with a mean follow-up of 37 months. Smokers had significantly worse subjective outcome measures and worse side-to-side difference in anterior translation compared to non-smokers (2.68 mm vs 1.89 mm, respectively). In 2 studies, smokers were found to have a significantly higher risk of developing an infection and VTE (venous thromboembolism) post-operatively. The evidence for the effect of smoking on risk for subsequent re-tear is mixed. No study reported a higher rate of development of radiographic knee osteoarthritis among smokers compared to nonsmokers. Conclusions: Cigarette smoke is associated with significantly worse clinical outcome scores, an increase in anterior translation, and increased complication rates after ACL reconstruction. These findings may help orthopaedic surgeons better inform their patients about the potential negative effects of smoking on the outcomes of ACL reconstruction. Level of Evidence: Therapeutic Level IV.

Sports reporting: a comprehensive review of the medical literature regarding North American professional sports.

Abstract Background: The increased physical demands of professional athletes predispose this patient population to a unique set of injuries typically not seen in the general population. This systematic literature review investigates the nature of injury reporting (both orthopedic and nonorthopedic conditions) in the medical literature of professional athletes in the National Football League (NFL), Major League Baseball (MLB), the National Basketball Association (NBA), and the National Hockey League (NHL). Rigorous reporting of sports injuries helps clinicians better understand disease mechanisms relevant to specific sports. Hypothesis: The nature of injury reporting will differ within each professional sport and reflect the anatomic emphasis of each sport. Methods: An electronic literature search of all publications addressing injuries and medical conditions among professional athletes in the NFL, MLB, NBA, and NHL was conducted using the Pubmed/Medline, Scopus, and Embase databases through January 2013. Retrieved publications were categorized by journal type, medical type, and area of focus. Results: A total of 536 publications met all inclusion criteria. There were a higher number of articles regarding the NFL (n = 211) and MLB (n = 216) when compared with the NBA (n = 34) or NHL (n = 75). The NFL had significantly more articles addressing nonorthopedic injuries/medical issues than were found with the MLB, NBA, or NHL (109 vs 75, 14, 41, respectively). Both the NFL (33 of 109, 30%) and NHL (6 of 41, 15%) had a relatively high percentage of articles regarding concussions/neurology, and MLB had a relatively high percentage of articles dedicated to vascular medicine (13 of 65, 20%). The proportion of publications dedicated to the knee/lower leg were highest in the NFL (29 of 102, 28%) and NBA (9 of 20, 45%), those dedicated to the shoulder/elbow were highest in MLB (113 of 151, 75%), and those dedicated to the hip/pelvis were highest in the NHL (16 of 34, 47%). Conclusions: The number and type of publications vary among the 4 professional sports leagues, and generally reflect the nature of the sport being played.

Surgically‑induced mouse models in the study of bone regeneration: Current models and future directions (Review)

Bone regeneration has been extensively studied over the past several decades. The surgically-induced mouse model is the key animal model for studying bone regeneration, of the various research strategies used. These mouse models mimic the trauma and recovery processes in vivo and serve as carriers for tissue engineering and gene modification to test various therapies or associated genes in bone regeneration. The present review introduces a classification of surgically induced mouse models in bone regeneration, evaluates the application and value of these models and discusses the potential development of further innovations in this field in the future.

Topical vancomycin and its effect on survival and migration of osteoblasts, fibroblasts, and myoblasts: An in vitro study

The purpose of this study was to examine the influence of topical vancomycin on cell migration and survival of tissue healing cells. Human osteoblasts, myoblasts and fibroblasts were exposed to vancomycin at concentrations of 1, 3, 6, or 12 mg/cm2 for either a 1-h or 48-h (continuous) duration. Continuous exposure to all vancomycin concentrations significantly reduced cell survival (<22% cells survived) and migration in osteoblasts and myoblasts (P < 0.001). 1-h vancomycin exposure reduced osteoblast and myoblast survival and migration only at 12 mg/cm2 (P < 0.001). Further in vivo studies are warranted to optimize the dosage of intrawound vancomycin.

Diabetes as an Independent Predictor for Extended Length of Hospital Stay and Increased Adverse Post-Operative Events in Patients Treated Surgically for Cervical Spondylotic Myelopathy

Background Diabetes as an independent driver of peri-operative outcomes, and whether its severity impacts indications is conflicted in the research. The purpose of this study is to evaluate diabetes as a predictor for postoperative outcomes in cervical spondylotic myelopathy (CSM) patients. Methods A retrospective review was performed of patients treated surgically for CSM (ICD-9 721.1) from 2010-2012 in the prospectively-collected American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database. Outcome measures were length of stay, and the presence of complications. Diabetic patients were stratified based on whether or not their diabetes was insulin- or non-insulin-dependent. Results A total of 5,904 surgical CSM patients were included, 1101 (19%) had diabetes. 722 (65%) were non-insulin-dependent diabetics, and 381 (35%) were insulin-dependent diabetics. Diabetes was found to be an independent predictor of extended LOS (OR: 1.878[2.262-1.559], p<0.001) as well as of developing a complication (OR: 1.666[2.217-1.253], p<0.001) after controlling for associated variables like BMI. Type of diabetes (insulin- vs. non-insulin-dependent) showed little significant difference between the groups (p>0.05), however, patients with insulin-dependent diabetes were associated with an increased incidence of wound complications (p=0.027); severity of diabetes was not associated with any other individual complications. Conclusions Type and severity of diabetes is not a predictor for complication. Diabetes is associated with extended LOS and peri-operative morbidity. Level of evidence: Class 2b. Clinical relevance: Our findings support the view of many spine surgeons, who believe that diabetes has a negative impact on the outcome of surgery for CSM. Our findings support those cohort studies that found an association between diabetes and worst post-operative outcomes following surgical treatment of CSM. These findings lend support to the importance of monitoring preoperative serum glucose levels, as prevention of peri-operative hyperglycemia has been linked to improved postoperative outcomes in spine, joint and colon surgery.

Variation in Diagnoses for Hip Arthroplasty Among New York State Hospitals: Implications for the Comprehensive Care for Joint Replacement Model

BACKGROUND The Comprehensive Care for Joint Replacement model is designed to minimize costs and improve quality for Medicare patients undergoing joint arthroplasty. The cost of hip arthroplasty (HA) episode varies depending on the preoperative diagnosis and is greater for fracture than for osteoarthritis. Hospitals that perform a higher percentage of HA for OA may therefore have an advantage in the Comprehensive Care for Joint Replacement model. The purposes of this study are to (1) determine the variability in underlying diagnosis for HA in New York State hospitals, and (2) determine hospital characteristics, such as volume, associated with this. METHODS The New York Statewide Planning and Research Cooperative System database was used to identify 127,206 primary HA procedures from 2010 to 2014. The data included underlying diagnoses, age, length of stay, and total charges. Hospitals were categorized by volume and descriptive statistics were used. RESULTS OA was the underlying diagnosis for HA for 74.2% of all patients; this was significantly higher for high-volume (89.30%) and medium-volume (74.9%) hospitals than for low-volume hospitals (58.4%, P < .05). HA for fracture was significantly more common at low-volume hospitals (32.4%) compared to medium-volume (18.0%) and high-volume (4.7%) hospitals (P < .05). Length of stay was significantly greater at low-volume hospitals for all diagnoses. CONCLUSION High-volume hospitals perform a higher ratio of HA cases for OA compared to fracture, which may lead to advantages in patient outcomes and cost. The variation in underlying diagnosis between hospitals has financial implications and underscores the need for HAs to be risk stratified by preoperative diagnosis.